4.1. Therapeutic indications

Protopic 0.03% ointment is indicated in adults, adolescents and children from the age of 2 years.

Flare treatment

Adults and adolescents (16 years of age and above)

Treatment of moderate to severe atopic dermatitis in adults who are not adequately responsive to or are intolerant of conventional therapies such as topical corticosteroids.

Children (2 years of age and above)

Treatment of moderate to severe atopic dermatitis in children who failed to respond adequately to conventional therapies such as topical corticosteroids.

Maintenance treatment

Treatment of moderate to severe atopic dermatitis for the prevention of flares and the prolongation of flare-free intervals in patients experiencing a high frequency of disease exacerbations (i.e. occurring 4 or more times per year) who have had an initial response to a maximum of 6 weeks treatment of twice daily tacrolimus ointment (lesions cleared, almost cleared or mildly affected).

4.2. Posology and method of administration

Protopic treatment should be initiated by physicians with experience in the diagnosis and treatment of atopic dermatitis.

Protopic is available in two strengths, Protopic 0.03% and Protopic 0.1% ointment.

Posology

Flare treatment

Protopic can be used for short-term and intermittent long-term treatment. Treatment should not be continuous on a long-term basis.

Protopic treatment should begin at the first appearance of signs and symptoms. Each affected region of the skin should be treated with Protopic until lesions are cleared, almost cleared or mildly affected.

Thereafter, patients are considered suitable for maintenance treatment (see below). At the first signs of recurrence (flares) of the disease symptoms, treatment should be re-initiated.

Adults and adolescents (16 years of age and above)

Treatment should be started with Protopic 0.1% twice a day and treatment should be continued until clearance of the lesion. If symptoms recur, twice daily treatment with Protopic 0.1% should be restarted. An attempt should be made to reduce the frequency of application or to use the lower strength Protopic 0.03% ointment if the clinical condition allows.

Generally, improvement is seen within one week of starting treatment. If no signs of improvement are seen after two weeks of treatment, further treatment options should be considered.

Elderly

Specific studies have not been conducted in older people. However, the clinical experience available in this patient population has not shown the necessity for any dosage adjustment.

Paediatric population

Children (2 years of age and above) should use the lower strength Protopic 0.03% ointment.

Treatment should be started twice a day for up to three weeks. Afterwards the frequency of application should be reduced to once a day until clearance of the lesion (see section 4.4).

Protopic ointment should not be used in children aged below 2 years until further data are available.

Maintenance treatment

Patients who are responding to up to 6 weeks treatment using tacrolimus ointment twice daily (lesions cleared, almost cleared or mildly affected) are suitable for maintenance treatment.

Adults and adolescents (16 years of age and above) Adult patients should use Protopic 0.1% ointment.

Protopic ointment should be applied once a day twice weekly (e.g. Monday and Thursday) to areas commonly affected by atopic dermatitis to prevent progression to flares. Between applications there should be 2–3 days without Protopic treatment.

After 12 months treatment, a review of the patient`s condition should be conducted by the physician and a decision taken whether to continue maintenance treatment in the absence of safety data for maintenance treatment beyond 12 months.

If signs of a flare reoccur, twice daily treatment should be re-initiated (see flare treatment section above).

Elderly

Specific studies have not been conducted in older people (see flare treatment section above).

Paediatric population

Children (2 years of age and above) should use the lower strength Protopic 0.03% ointment. Protopic ointment should be applied once a day twice weekly (e.g. Monday and Thursday) to areas commonly affected by atopic dermatitis to prevent progression to flares. Between applications there should be 2–3 days without Protopic treatment.

The review of the child`s condition after 12 months treatment should include suspension of treatment to assess the need to continue this regimen and to evaluate the course of the disease.

Protopic ointment should not be used in children aged below 2 years until further data are available.

Method of administration

Protopic ointment should be applied as a thin layer to affected or commonly affected areas of the skin.

Protopic ointment may be used on any part of the body, including face, neck and flexure areas, except on mucous membranes. Protopic ointment should not be applied under occlusion because this method of administration has not been studied in patients (see section 4.4).

4.3. Contraindications

Hypersensitivity to the active substance, macrolides in general, or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Exposure of the skin to sunlight should be minimised and the use of ultraviolet (UV) light from a solarium, therapy with UVB or UVA in combination with psoralens (PUVA) should be avoided during use of Protopic ointment (see section 5.3).Physicians should advise patients on appropriate sun protection methods, such as minimisation of the time in the sun, use of a sunscreen product and covering of the skin with appropriate clothing. Protopic ointment should not be applied to lesions that are considered to be potentially malignant or pre-malignant. The development of any new change different from previous eczema within a treated area should be reviewed by the physician.

The use of tacrolimus ointment is not recommended in patients with a skin barrier defect, such as Netherton's syndrome, lamellar ichthyosis, generalized erythroderma, pyoderma gangrenosum or cutaneous Graft Versus Host Disease. These skin conditions may increase systemic absorption of tacrolimus. Post-marketing cases of increased tacrolimus blood level have been reported in these conditions. Protopic should not be used in patients with congenital or acquired immunodeficiencies or in patients on therapy that cause immunosuppression.

Care should be exercised if applying Protopic to patients with extensive skin involvement over an extended period of time, especially in children (see section 4.2). Patients, particularly paediatric patients should be continuously evaluated during treatment with Protopic with respect to the response to treatment and the continuing need for treatment. After 12 months this evaluation should include suspension of Protopic treatment in paediatric patients (see section 4.2). The effect of treatment with Protopic ointment on the developing immune system of children aged below 2 years has not been established (see section 4.1).

Protopic contains the active substance tacrolimus, a calcineurin inhibitor. In transplant patients, prolonged systemic exposure to intense immunosuppression following systemic administration of calcineurin inhibitors has been associated with an increased risk of developing lymphomas and skin malignancies. Patients with atopic dermatitis treated with Protopic have not been found to have significant systemic tacrolimus levels and the role of local immunosuppression is unknown. Based on the results of long-term studies and experience, a link between Protopic ointment treatment and development of malignancies has not been confirmed, but definitive conclusions cannot be drawn. It is recommended to use tacrolimus ointment at the lowest strength and the lowest frequency for the shortest duration necessary as determined by the physician's evaluation of the clinical condition (see section 4.2).

Lymphadenopathy was uncommonly (0.8%) reported in clinical trials. The majority of these cases were related to infections (skin, respiratory tract, tooth) and resolved with appropriate antibiotic therapy. Lymphadenopathy present at initiation of therapy should be investigated and kept under review. In case of persistent lymphadenopathy, the aetiology of the lymphadenopathy should be investigated. In the absence of a clear aetiology for the lymphadenopathy or in the presence of acute infectious mononucleosis, discontinuation of Protopic should be considered. Patients who develop lymphadenopathy during treatment should be monitored to ensure that the lymphadenopathy resolves.

Patients with atopic dermatitis are predisposed to superficial skin infections. Protopic ointment has not been evaluated for its efficacy and safety in the treatment of clinically infected atopic dermatitis. Before commencing treatment with Protopic ointment, clinical infections at treatment sites should be cleared. Treatment with Protopic is associated with an increased risk of folliculitis and herpes viral infections (herpes simplex dermatitis [eczema herpeticum], herpes simplex [cold sores], Kaposi's varicelliform eruption) (see section 4.8). In the presence of these infections, the balance of risks and benefits associated with Protopic use should be evaluated.

Emollients should not be applied to the same area within 2 hours of applying Protopic ointment. Concomitant use of other topical preparations has not been assessed. There is no experience with concomitant use of systemic steroids or immunosuppressive agents.

Care should be taken to avoid contact with eyes and mucous membranes. If accidentally applied to these areas, the ointment should be thoroughly wiped off and/or rinsed off with water.

The use of Protopic ointment under occlusion has not been studied in patients. Occlusive dressings are not recommended.

As with any topical medicinal product, patients should wash their hands after application if the hands are not intended for treatment.

Tacrolimus is extensively metabolised in the liver and although blood concentrations are low following topical therapy, the ointment should be used with caution in patients with hepatic failure (see section 5.2).

Excipients warnings

Protopic ointment contains butylhydroxytoluene (E321) as an excipient, which may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.

4.5. Interaction with other medicinal products and other forms of interaction

Formal topical drug interaction studies with tacrolimus ointment have not been conducted.

Tacrolimus is not metabolised in human skin, indicating that there is no potential for percutaneous interactions that could affect the metabolism of tacrolimus.

Systemically available tacrolimus is metabolised via the hepatic Cytochrome P450 3A4 (CYP3A4). Systemic exposure from topical application of tacrolimus ointment is low (<1.0 ng/ml) and is unlikely to be affected by concomitant use of substances known to be inhibitors of CYP3A4. However, the possibility of interactions cannot be ruled out and the concomitant systemic administration of known CYP3A4 inhibitors (e.g. erythromycin, itraconazole, ketoconazole and diltiazem) in patients with widespread and/or erythrodermic disease should be done with caution.

Paediatric population

An interaction study with protein-conjugated vaccine against Neisseria menigitidis serogroup C has been investigated in children aged 2-11 years. No effect on immediate response to vaccination, the generation of immune memory, or humoral and cell-mediated immunity has been observed (see section 5.1).

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of tacrolimus ointment in pregnant women. Studies in animals have shown reproductive toxicity following systemic administration (see section 5.3). The potential risk for humans is unknown.

Protopic ointment should not be used during pregnancy unless clearly necessary.

Breast-feeding

Human data demonstrate that, after systemic administration, tacrolimus is excreted into breast milk. Although clinical data have shown that systemic exposure from application of tacrolimus ointment is low, breast-feeding during treatment with Protopic ointment is not recommended.

Fertility

There are no fertility data available.

4.7. Effects on ability to drive and use machines

Protopic ointment has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

In clinical studies approximately 50% of patients experienced some type of skin irritation adverse reaction at the site of application. Burning sensation and pruritus were very common, usually mild to moderate in severity and tended to resolve within one week of starting treatment. Erythema was a common skin irritation adverse reaction. Sensation of warmth, pain, paraesthesia and rash at the site of application were also commonly observed. Alcohol intolerance (facial flushing or skin irritation after consumption of an alcoholic beverage) was common.

Patients may be at an increased risk of folliculitis, acne and herpes viral infections.

Adverse reactions with suspected relationship to treatment are listed below by system organ class.

Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Class

Very Common

≥1/10

Common

≥1/100, <1/10

Uncommon

≥1/1000, <1/100

Not known (cannot be estimated from the available data)

Infections and infestations

Local skin infection regardless of specific aetiology including but not limited to:

Eczema herpeticum,

Folliculitis,

Herpes simplex,

Herpes virus infection,

Kaposi's varicelliform eruption*

Ophthalmic

Herpes

Infection*

Metabolism and nutrition disorders

Alcohol intolerance (facial flushing or skin irritation after consumption of an alcoholic beverage)

Nervous system disorders

Paraesthesias and dysaesthesias (hyperaesthesia, burning sensation)

Skin and subcutaneous tissue disorders

Pruritus

Acne*

Rosacea*

Lentigo*

General disorders and administration site conditions

Application site burning,

Application site pruritus

Application site warmth,

Application site erythema,

Application site pain,

Application site irritation,

Application site paraesthesia,

Application site rash

Application site oedema*

Investigations

Drug level increased* (see section 4.4)

*The adverse reaction has been reported during post-marketing experience

Maintenance treatment

In a study of maintenance treatment (twice weekly treatment) in adults and children with moderate and severe atopic dermatitis the following adverse events were noted to occur more frequently than in the control group: application site impetigo (7.7% in children) and application site infections (6.4% in children and 6.3% in adults).

Paediatric population

Frequency, type and severity of adverse reactions in children are similar to those reported in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance Website: www.hpra.ie .

4.9. Overdose

Overdosage following topical administration is unlikely.

If ingested, general supportive measures may be appropriate. These may include monitoring of vital signs and observation of clinical status. Due to the nature of the ointment vehicle, induction of vomiting or gastric lavage is not recommended.